NO334948B1 - Composition for use in the therapeutic treatment of overactive bladder, comprising acetic acid aniline derivative as active ingredient - Google Patents
Composition for use in the therapeutic treatment of overactive bladder, comprising acetic acid aniline derivative as active ingredient Download PDFInfo
- Publication number
- NO334948B1 NO334948B1 NO20052691A NO20052691A NO334948B1 NO 334948 B1 NO334948 B1 NO 334948B1 NO 20052691 A NO20052691 A NO 20052691A NO 20052691 A NO20052691 A NO 20052691A NO 334948 B1 NO334948 B1 NO 334948B1
- Authority
- NO
- Norway
- Prior art keywords
- bladder
- active ingredient
- overactive bladder
- test
- composition
- Prior art date
Links
- 206010020853 Hypertonic bladder Diseases 0.000 title claims abstract description 43
- 208000009722 Overactive Urinary Bladder Diseases 0.000 title claims abstract description 43
- 208000020629 overactive bladder Diseases 0.000 title claims abstract description 43
- 239000004480 active ingredient Substances 0.000 title claims abstract description 30
- 239000000203 mixture Substances 0.000 title claims description 36
- 230000001225 therapeutic effect Effects 0.000 title claims description 7
- FHSWXOCOMAVQKE-UHFFFAOYSA-N phenylazanium;acetate Chemical class CC([O-])=O.[NH3+]C1=CC=CC=C1 FHSWXOCOMAVQKE-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- -1 2-aminothiazol-4-yl Chemical group 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 206010046543 Urinary incontinence Diseases 0.000 claims description 15
- 206010036018 Pollakiuria Diseases 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 150000003931 anilides Chemical class 0.000 claims description 6
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 5
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 5
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 claims description 3
- 238000012360 testing method Methods 0.000 abstract description 37
- 230000008602 contraction Effects 0.000 abstract description 34
- 230000000694 effects Effects 0.000 abstract description 16
- 230000001020 rhythmical effect Effects 0.000 abstract description 15
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 abstract description 11
- 229960004397 cyclophosphamide Drugs 0.000 abstract description 11
- 230000004648 relaxation of smooth muscle Effects 0.000 abstract description 7
- 238000005259 measurement Methods 0.000 abstract description 6
- 210000002700 urine Anatomy 0.000 abstract description 6
- 230000002040 relaxant effect Effects 0.000 abstract description 5
- 230000002485 urinary effect Effects 0.000 abstract description 5
- 231100000673 dose–response relationship Toxicity 0.000 abstract description 4
- 230000009467 reduction Effects 0.000 abstract description 2
- 230000003389 potentiating effect Effects 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 25
- 229940126062 Compound A Drugs 0.000 description 24
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 24
- 229940079593 drug Drugs 0.000 description 22
- 230000027939 micturition Effects 0.000 description 22
- 241000700159 Rattus Species 0.000 description 20
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- UMQUQWCJKFOUGV-VIFPVBQESA-N 4-[(2s)-3-(tert-butylamino)-2-hydroxypropoxy]-1,3-dihydrobenzimidazol-2-one Chemical compound CC(C)(C)NC[C@H](O)COC1=CC=CC2=C1NC(=O)N2 UMQUQWCJKFOUGV-VIFPVBQESA-N 0.000 description 8
- 230000008485 antagonism Effects 0.000 description 8
- AIXAANGOTKPUOY-UHFFFAOYSA-N carbachol Chemical compound [Cl-].C[N+](C)(C)CCOC(N)=O AIXAANGOTKPUOY-UHFFFAOYSA-N 0.000 description 8
- 229960004484 carbachol Drugs 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000001103 potassium chloride Substances 0.000 description 7
- 235000011164 potassium chloride Nutrition 0.000 description 7
- 230000004936 stimulating effect Effects 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 208000008589 Obesity Diseases 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 235000020824 obesity Nutrition 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 208000022934 urinary frequency Diseases 0.000 description 4
- 230000036318 urination frequency Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 241000700157 Rattus norvegicus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 210000000013 bile duct Anatomy 0.000 description 3
- 201000001883 cholelithiasis Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 208000001130 gallstones Diseases 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 201000001421 hyperglycemia Diseases 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 238000011552 rat model Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- QILVTBCJVNFIDP-NTISSMGPSA-N (1r)-2-[2-(4-aminophenyl)ethylamino]-1-phenylethanol;hydrochloride Chemical compound Cl.C1=CC(N)=CC=C1CCNC[C@H](O)C1=CC=CC=C1 QILVTBCJVNFIDP-NTISSMGPSA-N 0.000 description 2
- LUAUJCGKCGBAKA-NTISSMGPSA-N (1r)-2-[2-(4-nitrophenyl)ethylamino]-1-phenylethanol;hydrochloride Chemical compound Cl.C([C@H](O)C=1C=CC=CC=1)NCCC1=CC=C([N+]([O-])=O)C=C1 LUAUJCGKCGBAKA-NTISSMGPSA-N 0.000 description 2
- YWGDTDSOHPHFAQ-OAHLLOKOSA-N (2r)-2-hydroxy-n-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide Chemical compound O=C([C@H](O)C=1C=CC=CC=1)NCCC1=CC=C([N+]([O-])=O)C=C1 YWGDTDSOHPHFAQ-OAHLLOKOSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 206010066218 Stress Urinary Incontinence Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 208000000921 Urge Urinary Incontinence Diseases 0.000 description 2
- 206010046555 Urinary retention Diseases 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 230000003184 effect on constriction Effects 0.000 description 2
- 201000005577 familial hyperlipidemia Diseases 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000036453 micturition reflex Effects 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 208000022170 stress incontinence Diseases 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 206010046494 urge incontinence Diseases 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DYCLHZPOADTVKK-UHFFFAOYSA-N 2-(2-azaniumyl-1,3-thiazol-4-yl)acetate Chemical compound NC1=NC(CC(O)=O)=CS1 DYCLHZPOADTVKK-UHFFFAOYSA-N 0.000 description 1
- JVMHULJEYUQYSH-UHFFFAOYSA-N 2-(4-nitrophenyl)ethylazanium;chloride Chemical compound Cl.NCCC1=CC=C([N+]([O-])=O)C=C1 JVMHULJEYUQYSH-UHFFFAOYSA-N 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002329 Aneurysm Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 102100034159 Beta-3 adrenergic receptor Human genes 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000020446 Cardiac disease Diseases 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- QPCVHQBVMYCJOM-UHFFFAOYSA-N Propiverine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCCC)C(=O)OC1CCN(C)CC1 QPCVHQBVMYCJOM-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 210000000467 autonomic pathway Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 108010014502 beta-3 Adrenergic Receptors Proteins 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- MYTMXVHNEWBFAL-UHFFFAOYSA-L dipotassium;carbonate;hydrate Chemical compound O.[K+].[K+].[O-]C([O-])=O MYTMXVHNEWBFAL-UHFFFAOYSA-L 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000002350 laparotomy Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960005434 oxybutynin Drugs 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 210000005037 parasympathetic nerve Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229960003510 propiverine Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 206010041232 sneezing Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
Abstract
Remedium for overaktiv blære, omfattende som aktiv ingrediens (R)-2-(2-aminotiazol-4-yl)-4'-[2[(2-hydroksy-2-fenyletyl)amino]etyl]eddiksyreanilid eller salt av dette, viser en potent blærerelakserende virkning i "test for relaksasjon av glatte muskler i isolert rotteblære", doseavhengig reduksjon i kontraksjonsfrekvensen ved rytmiske blærekontraksjoner i "test for måling av rytmisk blærekontraksjon hos rotte", og forlenger urineringsintervallene i "test for måling av urineringsfunksjon med overaktiv blære forårsaket av syklofosfamid i rotte som modell". Disse virkninger gjør forbindelsen over anvendelig som et remedium for overaktiv blære.Remedy for overactive bladder comprising as active ingredient (R) -2- (2-aminothiazol-4-yl) -4 '- [2 [(2-hydroxy-2-phenylethyl) amino] ethyl] acetic anilide or salt thereof, shows a potent bladder relaxant effect in "isolated rat bladder smooth muscle relaxation test", dose-dependent reduction in contraction rate in rhythmic bladder contractions in "rat rhythmic bladder contraction test", and prolongs urinary interruptions in urine bladder test for measurement caused by rat cyclophosphamide as a model ". These effects make the compound above useful as a remedy for overactive bladder.
Description
Teknisk område Technical area
Denne oppfinnelse angår en sammensetning for anvendelse ved behandling av overaktiv blære, omfattende (R)-2-(2-aminotiazol-4-yl)-4'-[2-[(2-hydroksy-2-fenyletyl)amino]etyl]-eddiksyreanilid eller et salt av dette som en aktiv ingrediens. This invention relates to a composition for use in the treatment of overactive bladder, comprising (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl] -acetic anilide or a salt thereof as an active ingredient.
Bakgrunnsteknikk Background technology
Blæren hos pattedyr er under en tosidig kontroll av autonome nerver, og detrusor slapper av via en adrenalin-p-reseptor ved stimulering av sympatisk nerve under urinering, samtidig som den ved uttømming av urin trekker seg sammen via en muskarinreseptor gjennom stimulering av parasympatisk nerve. Som en sammensetning for overaktiv blære når den tosidige kontroll som sådan er ubalansert, har det hittil oftest vært anvendt antikolinerge midler som propiverinhydrogenklorid og oksybutyninhydrogenklorid. Imidlertid er det gjenstridige tilfeller som ikke reagerer på slike forbindelser, og det er bivirkninger forårsaket av antikolinerge midler, så som urineringsdysfunksjon og tørr munn, og derfor er status i dag at det ikke alltid oppnås tilfredsstillende kliniske resultater. The bladder in mammals is under bilateral control of autonomic nerves, and the detrusor relaxes via an epinephrine-p receptor by stimulation of the sympathetic nerve during urination, while at the same time when emptying urine it contracts via a muscarinic receptor through stimulation of the parasympathetic nerve. As a composition for overactive bladder when the bilateral control as such is unbalanced, anticholinergic agents such as propiverine hydrogen chloride and oxybutynin hydrogen chloride have been most often used to date. However, there are stubborn cases that do not respond to such compounds, and there are side effects caused by anticholinergic agents, such as urinary dysfunction and dry mouth, and therefore the status today is that satisfactory clinical results are not always achieved.
Videre, som et resultat av et større antall eldre mennesker i befolkningen i de senere år, så er antallet pasienter som lider av overaktiv blære økt år for år, og i lys av pasientenes livskvalitet, så har det vært et kraftig behov for utvikling av nye medikamenter. Furthermore, as a result of a greater number of elderly people in the population in recent years, the number of patients suffering from overactive bladder has increased year by year, and in light of the patients' quality of life, there has been a strong need for the development of new medications.
De foreliggende oppfinnere rapporterte i eksempel 41 i offentlig tilgjengelig internasjonal søknad WO 99/20607 at (R)-2-(2-aminotiazol-4-yl)-4'-[2-[(2-hydroksy-2-fenyletyl)amino]etyl]eddiksyreaniliddihydrogenklorid har både en gunstig virkning på insulinsekresjon og en forsterkende virkning for insulinsensitivitet, og dessuten har det virkning mot fedme og hyperlipemi, slik at det er en anvendelig forbindelse for diabetes mellitus, men det er verken antydet eller beskrevet terapeutisk anvendelse for overaktiv blære (se patentpublikasjon 1). The present inventors reported in Example 41 of publicly available international application WO 99/20607 that (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino ]ethyl]acetic acid anilide dihydrogen chloride has both a beneficial effect on insulin secretion and an enhancing effect on insulin sensitivity, and furthermore it has an effect against obesity and hyperlipemia, so that it is a useful compound for diabetes mellitus, but there is neither suggested nor described therapeutic use for overactive bladder (see patent publication 1).
Imidlertid angår offentlig tilgjengelig internasjonal søknad WO 98/07445 et middel for forhindring og behandling av urineringsfrekvens og urininkontinens hvor midlet inneholder som en aktiv ingrediens et legemiddel som har en stimulerende virkning på en p3-adrenalinreseptor, og det nevnes at CGP-12177A representert med følgende kjemiske strukturformel, har en relakserende virkning på blæren (se patentpublikasjon 2). CGP-12,177 A har vært kjent som et selektivt legemiddel med en stimulerende virkning på en p3-adrenalinreseptor (se ikke-patentpublikasjoner 1 og 2). However, publicly available international application WO 98/07445 relates to an agent for the prevention and treatment of urinary frequency and urinary incontinence where the agent contains as an active ingredient a drug that has a stimulating effect on a p3-adrenaline receptor, and it is mentioned that CGP-12177A is represented by the following chemical structural formula, has a relaxing effect on the bladder (see patent publication 2). CGP-12,177 A has been known as a selective drug with a stimulatory effect on a p3-adrenaline receptor (see non-patent publications 1 and 2).
I offentlig tilgjengelig internasjonal søknad WO 99/31045 nevnes at forbindelser representert med den følgende formel har en stimulerende virkning på en p3-adrenalin-reseptor og er et middel for forhindring eller behandling av sykdommer forårsaket av fedme, hyperglykemi og akselerert bevegelse av tarmkanal og sykdommer forårsaket av urineringsfrekvens eller urininkontinens, melankoli, gallesten eller akselerert bevegelse i gallekanal (se patentpublikasjon 3). In publicly available international application WO 99/31045 it is mentioned that compounds represented by the following formula have a stimulating effect on a p3-adrenaline receptor and are a means of preventing or treating diseases caused by obesity, hyperglycemia and accelerated movement of the intestinal tract and diseases caused by urinary frequency or urinary incontinence, melancholy, gallstones or accelerated movement in the bile duct (see patent publication 3).
(I formelen er R<1>en hydroksylgruppe, en lavere alkylgruppe, en aralkoksygruppe, aminogruppe, etc, R<2>er hydroksylgruppe eller lavere alkylgruppe, R3 er hydrogenatom eller halogenatom, hver R<4>og R<5>er hydrogenatom, halogenatom eller en lavere alkylgruppe, og A er en lavere alkylengruppe). (In the formula, R<1> is a hydroxyl group, a lower alkyl group, an aralkyl group, amino group, etc, R<2> is a hydroxyl group or a lower alkyl group, R3 is a hydrogen atom or a halogen atom, each R<4> and R<5> is a hydrogen atom , halogen atom or a lower alkyl group, and A is a lower alkylene group).
I offentlig tilgjengelig internasjonal søknad WO 99/52856 nevnes at forbindelser representert med den følgende formel har en stimulerende virkning på en p3-adrenalin-reseptor og er et middel for forhindring eller behandling av sykdommer forårsaket av fedme, hyperglykemi og akselerert bevegelse av tarmkanal og sykdommer forårsaket av urineringsfrekvens eller urininkontinens, melankoli, gallesten eller akselerert bevegelse i gallekanal (se patentpublikasjon 4). In publicly available international application WO 99/52856 it is mentioned that compounds represented by the following formula have a stimulating effect on a p3-adrenaline receptor and are a means of preventing or treating diseases caused by obesity, hyperglycemia and accelerated movement of the intestinal tract and diseases caused by urinary frequency or urinary incontinence, melancholy, gallstones or accelerated movement in the bile duct (see patent publication 4).
(I formelen er R<1>hydrogenatom, en lavere alkylgruppe eller en aralkylgruppe, R<2>er hydrogenatom, en lavere alkylgruppe eller halogenatom, og A er oksygenatom eller imino-gruppe). (In the formula, R<1>is hydrogen atom, a lower alkyl group or an aralkyl group, R<2>is hydrogen atom, a lower alkyl group or halogen atom, and A is oxygen atom or imino group).
I offentlig tilgjengelig internasjonal søknad WO 00/02846 nevnes at forbindelser representert med den følgende formel haren stimulerende virkning på en p3-adrenalin-reseptor og er et middel for forhindring eller behandling av sykdommer forårsaket av fedme, hyperglykemi og akselerert bevegelse i tarmkanal og sykdommer forårsaket av urineringsfrekvens eller urininkontinens, melankoli, gallesten eller akselerert bevegelse i gallekanal (se patentpublikasjon 5). In publicly available international application WO 00/02846 it is mentioned that compounds represented by the following formula have a stimulating effect on a p3-adrenaline receptor and are a means for the prevention or treatment of diseases caused by obesity, hyperglycemia and accelerated motility in the intestinal tract and diseases caused by of urinary frequency or urinary incontinence, melancholy, gallstones or accelerated movement in the bile duct (see patent publication 5).
(I formelen er R<1>hydroksylgruppe etc; én av R<2>og R<3>er hydrogenatom, halogenatom, etc, og en annen er hydrogenatom; og R<4>er halogenatom, etc). (In the formula, R<1> is hydroxyl group etc; one of R<2> and R<3> is hydrogen atom, halogen atom, etc, and another is hydrogen atom; and R<4> is halogen atom, etc).
W002/00622 beskriver p3-adrenerge reseptoragonister for behandling av overaktiv blære, pollakiuri og urininkontinens. WO02/00622 describes β3-adrenergic receptor agonists for the treatment of overactive bladder, pollakiuria and urinary incontinence.
Patentpublikasjon 1: Offentlig tilgjengelig internasjonal søknad WO 99/20607. Patent publication 1: Publicly available international application WO 99/20607.
Patentpublikasjon 2:Offentlig tilgjengelig internasjonal søknad WO 98/07445. Patent publication 2: Publicly available international application WO 98/07445.
Patentpublikasjon 3: Offentlig tilgjengelig internasjonal søknad WO 99/31045. Patent publication 3: Publicly available international application WO 99/31045.
Patentpublikasjon 4: Offentlig tilgjengelig internasjonal søknad WO 99/52856. Patent Publication 4: Publicly Available International Application WO 99/52856.
Patentpublikasjon 5: Offentlig tilgjengelig internasjonal søknad WO 00/02846. Ikke-patentpublikasjon 1: Drugs of the Future, 1993, vol. 18, nr. 6, side 542. Ikke-patentpublikasjon 2: The American Society for Pharmacology and Experimental Therapeutics, 1993, vol. 44, side 1100. Patent publication 5: Publicly available international application WO 00/02846. Non-Patent Publication 1: Drugs of the Future, 1993, vol. 18, No. 6, page 542. Non-Patent Publication 2: The American Society for Pharmacology and Experimental Therapeutics, 1993, Vol. 44, page 1100.
Beskrivelse av oppfinnelsen Description of the invention
Oppfinnerne bak den foreliggende oppfinnelse har gjennomført intensive studier for å finne nye farmakologiske virkninger av (R)-2-(2-aminotiazol-4-yl)-4'-[2-[(2-hydroksy-2-fenyletyl)amino]etyl]eddiksyreanilid eller et salt av dette (heretter henvist til som "den aktive ingrediens ifølge den foreliggende oppfinnelse"), som er anvendelig som en sammensetning for diabetes mellitus, og som et resultat har de funnet at den aktive ingrediens ifølge den foreliggende oppfinnelse er anvendelig som en sammensetning spesielt for anvendelse ved behandling av overaktiv blære. I den foreliggende oppfinnelse, som definert ved kravene, er overaktiv blære definert som en sykdom hvor resultatet er hyppig trang til urinering. Selv om godartet prostatahyperplasi er eksemplifisert som én av årsakene til overaktiv blære, så er det mange tilfeller hvor årsaken er uklar, og de kalles idiopatisk overaktiv blære. Selv om overaktiv blære noen ganger er fulgt av hyppig urinering og urininkontinens, så er dette ikke begrenset til sykdommer som alltid følges av hyppig urinering og urininkontinens. I et tilfelle med svakt overaktiv blære er således en pasient følsom for trangen til å skulle urinere og har hyppig en følelse av å skulle urinere, men faktisk kan han/hun være i stand til å holde på urinen en stund. Selv i tilfeller med en svakt overaktiv blære er imidlertid en forbedring sterkt ønsket i lys av pasientens livskvalitet. På den annen side er en alvorlig overaktiv blære noen ganger fulgt av hyppig urinering og urininkontinens. Hyppig urinering er en tilstand hvor antallet ganger med urinering er mer enn det normale og er sagt å være ikke mindre enn ca. to ganger om natten og ikke mindre enn ca. 8 ganger i løpet av et døgn. Ved urininkontinens er det en ufrivillig urinlekkasje som defineres som en tilstand hvor det er et problem sosialt eller hygienisk. Urininkontinens klassifiseres i stressinkontinens som forekommer når abdominalt trykk påføres, som ved hosting og nysing, urgeinkontinens hvor det plutselig oppstår trang til å urinere og urin lekker før man når til toalettet, og urininkontinens av en blandet type hvor både stressinkontinens og urgeinkontinens er til stede. The inventors behind the present invention have carried out intensive studies to find new pharmacological effects of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino] ethyl]acetic acid anilide or a salt thereof (hereinafter referred to as "the active ingredient of the present invention"), which is useful as a composition for diabetes mellitus, and as a result, they have found that the active ingredient of the present invention is useful as a composition especially for use in the treatment of overactive bladder. In the present invention, as defined by the claims, overactive bladder is defined as a disease where the result is a frequent urge to urinate. Although benign prostatic hyperplasia is exemplified as one of the causes of overactive bladder, there are many cases where the cause is unclear, and they are called idiopathic overactive bladder. Although overactive bladder is sometimes accompanied by frequent urination and urinary incontinence, this is not limited to diseases that are always accompanied by frequent urination and urinary incontinence. Thus, in a case of slightly overactive bladder, a patient is sensitive to the urge to urinate and has a frequent feeling of needing to urinate, but in fact he/she may be able to hold the urine for some time. Even in cases with a slightly overactive bladder, however, an improvement is strongly desired in light of the patient's quality of life. On the other hand, a severely overactive bladder is sometimes accompanied by frequent urination and urinary incontinence. Frequent urination is a condition where the number of times you urinate is more than normal and is said to be no less than approx. twice a night and not less than approx. 8 times in a day. Urinary incontinence is an involuntary leakage of urine which is defined as a condition where there is a social or hygienic problem. Urinary incontinence is classified into stress incontinence which occurs when abdominal pressure is applied, such as when coughing and sneezing, urge incontinence where there is a sudden urge to urinate and urine leaks before reaching the toilet, and urinary incontinence of a mixed type where both stress incontinence and urge incontinence are present.
Det karakteristiske trekk ved den foreliggende oppfinnelse er at den aktive ingrediens ifølge den foreliggende oppfinnelse demper spesielt den hyppige forekomst av urineringstrang hos en pasient og antallet ganger med urinering, og urineringstilstanden bringes over i en mer normal tilstand. Det er underforstått at i henhold til den foreliggende oppfinnelse innbefatter overaktiv blære ikke bare resultatet av godartet prostatahyperplasi, men også det som følger med urineringstrang, urininkontinens og pollakiuri. The characteristic feature of the present invention is that the active ingredient according to the present invention particularly suppresses the frequent occurrence of the urge to urinate in a patient and the number of times of urination, and the state of urination is brought over to a more normal state. It is understood that according to the present invention, overactive bladder includes not only the result of benign prostatic hyperplasia, but also that which accompanies the urge to urinate, urinary incontinence and pollakiuria.
I henhold til patentpublikasjon 1, er den aktive ingrediens ifølge den foreliggende oppfinnelse anvendelig, i tillegg til behandling av diabetes, som et middel for å forhindre og behandle andre sykdommer hvor det er mulig å oppnå en forbedring i symptomer ved å redusere symptomer forbundet med fedme og hyperlipemi, så som arteriosklerose, iskemisk kardial sykdom som hjerteinfarkt og angina pectoris, hjernearteriesklerose som cerebralt infarkt, aneurisme, etc. Imidlertid er det verken beskrevet eller over hodet antydet at den aktive ingrediens ifølge den foreliggende oppfinnelse er anvendelig som en sammensetning for overaktiv blære. According to patent publication 1, the active ingredient according to the present invention is applicable, in addition to the treatment of diabetes, as a means of preventing and treating other diseases where it is possible to achieve an improvement in symptoms by reducing symptoms associated with obesity and hyperlipemia, such as arteriosclerosis, ischemic cardiac disease such as myocardial infarction and angina pectoris, cerebral arteriosclerosis such as cerebral infarction, aneurysm, etc. However, it is neither described nor suggested that the active ingredient of the present invention is applicable as a composition for overactive bladder .
I patentpublikasjon 2 er anvendelse for overaktiv blære heller ikke nevnt. I patentpublikasjon 2 er det kun angitt at CGP-12177A har en relakserende virkning på blæren ved at den er en forbindelse som har en selektiv stimulerende virkning på en p3-adrenalin-reseptor. Sammenlignet med CGP-12177A har imidlertid den aktive ingrediens ifølge den foreliggende oppfinnelse en langt sterkere relakserende virkning på blæren. Dessuten er det i patentpublikasjon 2 ingen beskrivelse av tester in vivo som viser anvendeligheten ved behandling av overaktiv blære, så som "test for måling av rytmisk blærekontraksjon hos rotter" og "testmodell for måling av urineringsfunksjon ved syklofosfamid-indusert overaktiv blære hos rotter". In patent publication 2, application for overactive bladder is not mentioned either. In patent publication 2, it is only stated that CGP-12177A has a relaxing effect on the bladder in that it is a compound that has a selective stimulating effect on a p3-adrenaline receptor. Compared to CGP-12177A, however, the active ingredient according to the present invention has a far stronger relaxing effect on the bladder. Moreover, in patent publication 2, there is no description of tests in vivo that show their applicability in the treatment of overactive bladder, such as "test for measuring rhythmic bladder contraction in rats" and "test model for measuring urination function in cyclophosphamide-induced overactive bladder in rats".
Videre er anvendelse for overaktiv blære heller ikke nevnt i patentpublikasjoner 3 til 5. Forbindelser nevnt i patentpublikasjoner 3 til 5 og den aktive ingrediens ifølge den foreliggende oppfinnelse er forskjellige i sin fundamentale struktur ved at forbindelsene nevnt i publikasjonene alltid har en fenolring men ingen tiazolring, og de har heller ingen amidbinding. I tillegg er det i patentpublikasjoner 3 til 5 ingen beskrivelse av tester in vivo som viser anvendeligheten ved behandling av overaktiv blære, så som "test for måling av rytmisk blærekontraksjon hos rotter" og "testmodell for måling av urineringsfunksjon ved syklofosfamid-indusert overaktiv blære hos rotter". Furthermore, application for overactive bladder is also not mentioned in patent publications 3 to 5. Compounds mentioned in patent publications 3 to 5 and the active ingredient according to the present invention differ in their fundamental structure in that the compounds mentioned in the publications always have a phenol ring but no thiazole ring, and they also have no amide bond. In addition, in patent publications 3 to 5 there is no description of tests in vivo that show the applicability in the treatment of overactive bladder, such as "test for measuring rhythmic bladder contraction in rats" and "test model for measuring urinary function in cyclophosphamide-induced overactive bladder in roots".
Den foreliggende oppfinnelse skal nå illustreres detaljert nedenfor. The present invention will now be illustrated in detail below.
I den foreliggende oppfinnelse er (R)-2-(2-aminotiazol-4-yl)-4'-[2-[(2-hydroksy-2-fenyletyl)amino]etyl]eddiksyreanilid eller et salt av dette, en aktiv ingrediens. Det karakteristiske trekk ved den foreliggende oppfinnelse er at den aktive ingrediens ifølge den foreliggende oppfinnelse er funnet å være anvendelig som en sammensetning for anvendelse ved behandling av overaktiv blære, hvilket er en ny anvendelse. In the present invention, (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic anilide or a salt thereof, an active ingredient. The characteristic feature of the present invention is that the active ingredient according to the present invention has been found to be usable as a composition for use in the treatment of overactive bladder, which is a new application.
Det er særlig foretrukket at den aktive ingrediens ifølge den foreliggende oppfinnelse er en fri substans som ikke har noe salt. Imidlertid kan den danne salt med en syre, og eksempler på salter er syreaddisjonssalter med en mineralsyre som saltsyre, hydrogen-bromsyre, hydrogenjodsyre, svovelsyre, salpetersyre og fosforsyre, og organiske syrer som maursyre, eddiksyre, propionsyre, oksalsyre, malonsyre, ravsyre, fumarsyre, maleinsyre, melkesyre, eplesyre, sitronsyre, vinsyre, karbonsyre, pikrinsyre, metansulfonsyre, etan-sulfonsyre og glutaminsyre. Den aktive ingrediens ifølge den foreliggende oppfinnelse som har et salt, kan lett fremstilles av et fritt stoff ved en vanlig saltdannende reaksjon. Den aktive ingrediens ifølge den foreliggende oppfinnelse innbefatter videre hydrater, solvater og polymorfisme. Den aktive ingrediens som ikke er en del av oppfinnelsen innbefatter videre farmakologisk akseptable forløpermedikamenter. Med hensyn til en gruppe for å danne forløpermedikamentet, kan det som eksempel nevnes det som er angitt i Prog. Med. 5, 2157-2161 (1985) og "Iyakuhin no Kaihatsu" (Utvikling av legemidler) (Hirokawa Shoten, 1990), vol. 7, Molecule Design, 163-198. It is particularly preferred that the active ingredient according to the present invention is a free substance that has no salt. However, it can form a salt with an acid, and examples of salts are acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid , maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid. The active ingredient according to the present invention which has a salt can easily be prepared from a free substance by a common salt-forming reaction. The active ingredient according to the present invention further includes hydrates, solvates and polymorphism. The active ingredient which is not part of the invention further includes pharmacologically acceptable precursor drugs. With regard to a group to form the precursor drug, it can be mentioned as an example what is indicated in Prog. With. 5, 2157-2161 (1985) and "Iyakuhin no Kaihatsu" (Development of Medicines) (Hirokawa Shoten, 1990), vol. 7, Molecule Design, 163-198.
Medikamentet som inneholder den aktive ingrediens ifølge den foreliggende oppfinnelse kan være i enhver form som er egnet for oral administrasjon, som tabletter, piller, kapsler, granuler, fortynnet pulver, etc, og for parenteral administrasjon, som inhaleringsmiddel, etc. Med hensyn til en fast blanding for oral administrasjon anvendes tabletter, fortynnet pulver, granuler, etc. I selve den faste blandingen blir én eller flere aktive ingredienser blandet med minst én inert eksipient slik som laktose, mannitol, glukose, hydroksypropylcellulose, mikrokrystallinsk cellulose, stivelse, polyvinylpyrrolidon og magnesiummetasilikataluminat. Blandingen kan inneholde et inert additiv, så som smøre-middel (for eksempel magnesiumstearat), desintegrerende middel (for eksempel natrium-karboksymetylstivelse), oppløseliggjørende middel, etc, tilsatt ved en vanlig metode. Tabletter og piller kan om nødvendig være overtrukket med sukkerbelegg eller med et intragastrisk eller enterisk beleggingsmiddel. En passende dose må bestemmes i hvert enkelt tilfelle ved å ta i betraktning symptomer, alder og kjønn, etc, hos pasienten som skal få administrert legemidlet. Vanligvis administreres fra ca. 0,01 mg/kg til 100 mg/kg pr. dag for en voksen når det gjelder oral administrasjon, og dette blir administrert enten alt på én gang eller ved å dele det i to eller fire. The medicament containing the active ingredient of the present invention may be in any form suitable for oral administration, such as tablets, pills, capsules, granules, diluted powder, etc., and for parenteral administration, such as inhalant, etc. With regard to a solid mixture for oral administration uses tablets, diluted powder, granules, etc. In the solid mixture itself, one or more active ingredients are mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and magnesium metasilicate aluminate . The mixture may contain an inert additive, such as lubricant (for example magnesium stearate), disintegrating agent (for example sodium carboxymethyl starch), solubilizing agent, etc., added by a conventional method. If necessary, tablets and pills can be coated with a sugar coating or with an intragastric or enteric coating agent. An appropriate dose must be determined in each individual case by taking into account the symptoms, age and sex, etc., of the patient who is to be administered the medicine. Usually administered from approx. 0.01 mg/kg to 100 mg/kg per day for an adult in terms of oral administration, and this is administered either all at once or by dividing it into two or four.
Den aktive ingrediens ifølge den foreliggende oppfinnelse kan lett bli fremstilt ved en fremgangsmåte nevnt i patentpublikasjon 1, men fordi fremgangsmåten for fremstilling av en fri substans, som er den foretrukne aktive ingrediens ifølge den foreliggende oppfinnelse, ikke er spesifikt nevnt der, så er en slik fremstillingsmetode vist i fremstillingseksemplene. En rute for fremstillingen kan illustreres som følger. The active ingredient according to the present invention can easily be produced by a method mentioned in patent publication 1, but because the method for producing a free substance, which is the preferred active ingredient according to the present invention, is not specifically mentioned there, such a manufacturing method shown in the manufacturing examples. A route for the manufacture can be illustrated as follows.
Fremstillingseksempler (Fremstillingsmåte for fremstilling av den aktive ingrediens ifølge den foreliggende oppfinnelse) Manufacturing examples (Manufacturing method for manufacturing the active ingredient according to the present invention)
Trinn 1 Step 1
Til en blanding av 5,90 kg 4-nitrofenyletylamin-monohydrogenklorid, 4,43 kg (R)-mandelsyre, 2,94 kg trietylamin og 22 liter N,N-dimetylformamid ble det tilsatt 3,93 kg hydroksybenztriazol og 5,58 kg l-(3-dimetylaminopropyl)-3-etylkarbodiimid-monohydrogenklorid (EDC) fulgt av omrøring ved ca. romtemperatur i 2 timer. Det ble tilsatt ytterligere EDC (0,28 kg) og blandingen ble omrørt ved romtemperatur over natten. Reaksjonsløsningen ble fortynnet med 110 liter vann og ekstrahert med etylacetat (60 liter, 30 liter). Det organiske lag ble i rekkefølge vasket med 60 liter 1 M vandig saltsyre, 60 liter 20% vannløsning av kaliumkarbonat og vann (60 liter, 60 liter) og konsentrert i vakuum ved 10 °C til 19 °C. Residuet ble oppløst i 35 liter toluen ved oppvarming ved 87 °C, avkjølt og omrørt ved 20 °C i løpet av én natt. De resulterende krystaller ble filtrert og vasket med 10 liter toluen. Dette ble tørket i vakuum, hvilket ga 7,66 kg (R)-2-hydroksy-N-[2-(4-nitrofenyl)etyl]-2-fenylacetamid som lysegule krystaller. To a mixture of 5.90 kg of 4-nitrophenylethylamine monohydrogen chloride, 4.43 kg of (R)-mandelic acid, 2.94 kg of triethylamine and 22 liters of N,N-dimethylformamide, 3.93 kg of hydroxybenztriazole and 5.58 kg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrogen chloride (EDC) followed by stirring at ca. room temperature for 2 hours. Additional EDC (0.28 kg) was added and the mixture was stirred at room temperature overnight. The reaction solution was diluted with 110 liters of water and extracted with ethyl acetate (60 liters, 30 liters). The organic layer was successively washed with 60 liters of 1 M aqueous hydrochloric acid, 60 liters of 20% aqueous potassium carbonate solution and water (60 liters, 60 liters) and concentrated in vacuo at 10°C to 19°C. The residue was dissolved in 35 liters of toluene by heating at 87 °C, cooled and stirred at 20 °C overnight. The resulting crystals were filtered and washed with 10 liters of toluene. This was dried in vacuo to give 7.66 kg of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide as pale yellow crystals.
'H-NMR (DMSO-cU, 400 MHz) 5 (ppm) = 2,87 (2H, t, J = 7,2 Hz), 3,30-3,46 (2H,m), 4,85 (1H, d, J = 4,8 Hz), 6,12 (1H, d, J = 4,8 Hz), 7,20-7,33 (5H, m), 7,40 (2H, d, J = 8,0 Hz), 8,04-8,12 (3H, m). FAB-MS m/z: 301 (M+H)<+>. 1H-NMR (DMSO-cU, 400 MHz) δ (ppm) = 2.87 (2H, t, J = 7.2 Hz), 3.30-3.46 (2H,m), 4.85 ( 1H, d, J = 4.8 Hz), 6.12 (1H, d, J = 4.8 Hz), 7.20-7.33 (5H, m), 7.40 (2H, d, J = 8.0 Hz), 8.04-8.12 (3H, m). FAB-MS m/z: 301 (M+H)<+>.
Trinn 2 Step 2
(R)-2-hydroksy-N-[2-(4-nitrofenyl)etyl]-2-fenylacetamid, 23 liter l,3-dimetyl-2-imidazlidinon og 23 liter tetrahydrofuran ble avkjølt til -18 °C og til dette ble det tilsatt dråpevis 49,4 kg IM bor-tetrahydrofuranløsning ved ikke høyere enn -7 °C. Etter dette ble temperaturen i blandingen hevet til 70 °C, fulgt av omrøring i 5 timer. Reaksjonsblandingen ble avkjølt til -12 °C og det ble tilsatt 2,9 kg metanol og 5,9 kg konsentrert saltsyre ved ikke over 5 °C. Etter omrøring ved 68 °C i 1 time ble blandingen konsentrert i vakuum inntil (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide, 23 liters of 1,3-dimethyl-2-imidazlidinone and 23 liters of tetrahydrofuran were cooled to -18 °C and to this 49.4 kg IM boron-tetrahydrofuran solution was added dropwise at no higher than -7 °C. After this, the temperature of the mixture was raised to 70 °C, followed by stirring for 5 hours. The reaction mixture was cooled to -12 °C and 2.9 kg of methanol and 5.9 kg of concentrated hydrochloric acid were added at no more than 5 °C. After stirring at 68 °C for 1 hour, the mixture was concentrated in vacuo until
mengden var blitt 50 liter. Det ble tilsatt en 30%-ig vannløsning (60 kg) av K2C03og 6 liter vann, fulgt av ekstrahering med 75 liter etylacetat. Det organiske lag ble vasket med 75 liter vann og konsentrert i vakuum. Til residuet ble det tilsatt isopropanol (75 liter) og blandingen ble oppløst ved 40 °C. Det ble tilsatt 2,46 kg konsentrert saltsyre for krystallisering, fulgt av omrøring ved 23 °C i løpet av én natt. Krystallene ble filtrert og vasket med 38 liter isopropanol. Det ble tørket i vakuum, hvilket ga 7,29 kg (R)-2-[[2-(4-nitrofenyl)etyl]amino]-l-fenyletanol-monohydrogenklorid. the quantity had become 50 litres. A 30% aqueous solution (60 kg) of K 2 CO 3 and 6 liters of water were added, followed by extraction with 75 liters of ethyl acetate. The organic layer was washed with 75 liters of water and concentrated in vacuo. To the residue was added isopropanol (75 litres) and the mixture was dissolved at 40°C. 2.46 kg of concentrated hydrochloric acid was added for crystallization, followed by stirring at 23°C overnight. The crystals were filtered and washed with 38 liters of isopropanol. It was dried in vacuo to give 7.29 kg of (R)-2-[[2-(4-nitrophenyl)ethyl]amino]-1-phenylethanol monohydrogen chloride.
^-NMR (DMSO-de, 400 MHz) 5 (ppm) = 3,00-3,08 (1H, m), 3,15-3,30 (5H, m), 5,00-5,05 (1H, m), 6,23 (1H, d, J = 4,0 Hz), 7,29-7,35 (1H, m), 7,36-7,43 (4H, m), 7,57 (2H, d, J = 8,4 Hz), 8,21 (2H, d, J = 8,4 Hz), 9,12 (2H, br). FAB-MS m/z: 287 (M+H)<+>. 3-NMR (DMSO-de, 400 MHz) δ (ppm) = 3.00-3.08 (1H, m), 3.15-3.30 (5H, m), 5.00-5.05 ( 1H, m), 6.23 (1H, d, J = 4.0 Hz), 7.29-7.35 (1H, m), 7.36-7.43 (4H, m), 7.57 (2H, d, J = 8.4 Hz), 8.21 (2H, d, J = 8.4 Hz), 9.12 (2H, br). FAB-MS m/z: 287 (M+H)<+>.
Trinn 3 Step 3
En blanding av 11,0 kg (R)-2-[[2-(4-nitrofenyl)etyl]amino]-l-fenyletanolmono-hydrogenklorid, 110 liter metanol og 1,20 kg vått 10% palladium-karbon (fuktegrad: 54,2%) ble omrørt i en hydrogenatmosfære inntil absorpsjonen av hydrogen stoppet. Reaksjonsløsningen ble filtrert og filtratet ble konsentrert i vakuum. Metanol (40 liter) ble tilsatt til residuet for å oppløse dette ved 40 °C, og krystallisering ble utført ved å tilsette 220 liter diisopropyleter, fulgt av omrøring ved 20 °C i løpet av én natt. Krystallene ble filtrert og vasket med 30 liter diisopropyleter. De ble tørket i vakuum, hvilket ga 9,43 kg (R)-2-[[2-(4-aminofenyl)etyl]amino]-l-fenyletanol-monohydrogenklorid. A mixture of 11.0 kg of (R)-2-[[2-(4-nitrophenyl)ethyl]amino]-1-phenylethanol mono-hydrogen chloride, 110 liters of methanol and 1.20 kg of wet 10% palladium carbon (moisture degree: 54.2%) was stirred in a hydrogen atmosphere until the absorption of hydrogen stopped. The reaction solution was filtered and the filtrate was concentrated in vacuo. Methanol (40 L) was added to the residue to dissolve it at 40 °C, and crystallization was carried out by adding 220 L of diisopropyl ether, followed by stirring at 20 °C overnight. The crystals were filtered and washed with 30 liters of diisopropyl ether. They were dried in vacuo to give 9.43 kg of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrogen chloride.
^-NMR (DMSO-de, 400 MHz) 5 (ppm) = 2,76-2,90 (2H, m), 2,95-3,16 (4H, m), 4,95-5,11 (3H, m), 6,20 (1H, d, J = 4,0 Hz), 6,53 (2H, d, J = 8,4 Hz), 6,89 (2H, d, J = 8,4 Hz), 7,28-7,43 (5H, m), 8,97 (1H, br), 9,29 (1H, br). FAB-MS m/z: 257 (M+H)<+>. 3-NMR (DMSO-de, 400 MHz) δ (ppm) = 2.76-2.90 (2H, m), 2.95-3.16 (4H, m), 4.95-5.11 ( 3H, m), 6.20 (1H, d, J = 4.0 Hz), 6.53 (2H, d, J = 8.4 Hz), 6.89 (2H, d, J = 8.4 Hz), 7.28-7.43 (5H, m), 8.97 (1H, br), 9.29 (1H, br). FAB-MS m/z: 257 (M+H)<+>.
Trinn 4 Step 4
l-(3-dimetylaminopropyl)-3-etylkarbodiimid-monohydrogenklorid (EDC) (5,76 g) ble tilsatt til en blanding av 8,00 g (R)-2-[[2-(4-aminofenyl)etyl]amino]-l-fenyletanol-monohydrogenklorid, 4,32 g 2-aminotiazol-4-yl-eddiksyre, 2,64 g konsentrert saltsyre og 120 ml vann ved romtemperatur, fulgt av omrøring i 1 time. En blandet oppløsning av 2,40 g natriumhydroksid og 40 ml vann ble tilsatt dråpevis til reaksjonsløsningen for at denne skulle krystallisere. De resulterende krystaller ble filtrert, vasket med vann og tørket i vakuum, hvilket ga 9,93 g (R)-2-(2-aminotiazol-4-yl)-4'-[2-[(2-hydroksy-2-fenyletyl)-amino]-etyl]eddiksyre-anilid (heretter kalt "forbindelse A"). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide monohydrogen chloride (EDC) (5.76 g) was added to a mixture of 8.00 g of (R)-2-[[2-(4-aminophenyl)ethyl]amino ]-1-phenylethanol monohydrogen chloride, 4.32 g of 2-aminothiazol-4-yl-acetic acid, 2.64 g of concentrated hydrochloric acid and 120 ml of water at room temperature, followed by stirring for 1 hour. A mixed solution of 2.40 g of sodium hydroxide and 40 ml of water was added dropwise to the reaction solution in order for it to crystallize. The resulting crystals were filtered, washed with water and dried in vacuo to give 9.93 g of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2- phenylethyl)-amino]-ethyl]acetic anilide (hereinafter referred to as "compound A").
^-NMR (DMSO-de, 500 MHz) 5 (ppm) = 1,60 (1H, s), 2,59-2,66 (4H, m), 2,68-2,80 (2H, m), 3,45 (2H, s), 4,59 (1H, br), 5,21 (1H, br), 6,30 (1H, s), 6,89 (2H, s), 7,11 (2H, d, J = 8,5 Hz), 7,19-7,23 (1H, m), 7,27-7,33 (4H, m), 7,49 (2H, d, J = 8,5 Hz), 9,99 (1H, s). FAB-MS m/z: 397 (M+H)<+>. 3-NMR (DMSO-de, 500 MHz) δ (ppm) = 1.60 (1H, s), 2.59-2.66 (4H, m), 2.68-2.80 (2H, m) , 3.45 (2H, s), 4.59 (1H, br), 5.21 (1H, br), 6.30 (1H, s), 6.89 (2H, s), 7.11 ( 2H, d, J = 8.5 Hz), 7.19-7.23 (1H, m), 7.27-7.33 (4H, m), 7.49 (2H, d, J = 8, 5 Hz), 9.99 (1H, p). FAB-MS m/z: 397 (M+H)<+>.
Beste måte for utførelse av oppfinnelsen Best method for carrying out the invention
Den foreliggende oppfinnelse skal nå bli spesifikt illustrert ved hjelp av de følgende eksempler. The present invention will now be specifically illustrated by means of the following examples.
Eksempel 1 (Test for relaksasjon av glatt muskel i isolert rotteblære) Example 1 (Test for relaxation of smooth muscle in isolated rat bladder)
Testmetode Test method
Testen ble utført med henvisning til The Journal of Urology, 1999, vol. 161, side 680. The test was performed with reference to The Journal of Urology, 1999, vol. 161, page 680.
Hannrotter av Wistar-arten som var 10-11 uker gamle ble avlivet ved deplesjon, hele blæren ble isolert ved laparotomy og blæreseksjoner som hver var av størrelse ca. 3 x 10 mm ble tilberedt i en næringsløsning som var vel oksygenert med 95 % 02og 5 % C02Male Wistar rats that were 10-11 weeks old were euthanized by depletion, the entire bladder was isolated by laparotomy and bladder sections each of size approx. 3 x 10 mm were prepared in a nutrient solution that was well oxygenated with 95% O2 and 5% C02
(Krebs-Henseleit-løsning (118,4 mM NaCI, 4,7 mM KCI, 1,2 mM KH2P04; 1,2 mM MgS04, 2,5 mM CaCI2, 25,0 mM NaHC03og 11,1 mM glukose)). Seksjonene ble hengt opp i et Magnus-rør som inneholdt en næringsløsning (Krebs-Henseleit-løsning) ved 37 °C, og i dette ble det ført inn 95% 02og 5% Co2, stabilisert i 30-60 minutter ved å tilføre 1 g IO"<6>M karbachol (CCh) eller 40 mM kalsiumklorid (KCI) gjentatte ganger inntil det ble bekreftet at reaktiviteten overfor CCh eller KCI var blitt nesten konstant. Etter det var oppnådd en kontraksjon med IO"<6>M CCh eller 40 mM KCI, og den genererte spenning var stabilisert, ble et testmedikament (forbindelse A eller CGP-12,177A) administrert kumulativt i 10-foldig (Krebs-Henseleit solution (118.4 mM NaCl, 4.7 mM KCl, 1.2 mM KH 2 PO 4 ; 1.2 mM MgSO 4 , 2.5 mM CaCl 2 , 25.0 mM NaHCO 3 and 11.1 mM glucose)). The sections were suspended in a Magnus tube containing a nutrient solution (Krebs-Henseleit solution) at 37 °C, into which 95% O2 and 5% Co2 were introduced, stabilized for 30-60 minutes by adding 1 g 10"<6>M carbachol (CCh) or 40 mM calcium chloride (KCl) repeatedly until it was confirmed that the reactivity to CCh or KCl had become almost constant. After that a contraction was obtained with 10"<6>M CCh or 40 mM KCl, and the generated voltage was stabilized, a test drug (compound A or CGP-12,177A) was administered cumulatively in 10-fold
forhold med intervaller på ca. 10 minutter og relaksasjonsreaksjonen ble observert. Etterat det var observert at relaksasjonsreaksjonen var fullstendig ved maksimal konsentrasjon av testmedikament, ble det tilsatt IO"<4>M papaverin for å oppnå maksimum relaksasjon, og det ble beregnet en relaksasjonshastighet til det punkt hvor relaksasjonsreaksjonen var definert som 100%. relationship with intervals of approx. 10 minutes and the relaxation reaction was observed. After it was observed that the relaxation reaction was complete at the maximum concentration of test drug, 10"<4>M papaverine was added to achieve maximum relaxation, and a relaxation rate was calculated to the point where the relaxation reaction was defined as 100%.
Resultater Results
Som et resultat av testen over viste forbindelse A, som er den aktive ingrediens ifølge den foreliggende oppfinnelse, en sterk relaksasjonsvirkning i antagonismetesten ved kontraksjon med karbachol og i antagonismetesten ved kontraksjon med kaliumklorid i en test for relaksasjon av glatte muskler i isolert rotteblære. I tillegg viste forbindelse A en signifikant sterk relaksasjonsvirkning sammenlignet med CGP-12177A (sammenligningsforbindelse). As a result of the test above, compound A, which is the active ingredient according to the present invention, showed a strong relaxation effect in the antagonism test by contraction with carbachol and in the antagonism test by contraction with potassium chloride in a test for relaxation of smooth muscles in isolated rat bladder. In addition, compound A showed a significantly strong relaxation effect compared to CGP-12177A (comparison compound).
Relaksasjonshastigheter avhengig av medikamentkonsentrasjon av forbindelse A, som er den aktive ingrediens ifølge den foreliggende oppfinnelse, og av sammenligningsforbindelsen er vist på figur 1 (antagonismetest ved kontraksjon med karbachol) og figur 2 (antagonismetest ved kontraksjon med kaliumklorid). Videre, EC50 og maksimum relaksasjonsgrad for det testede medikament i antagonismetesten ved kontraksjon med karbachol er vist i tabell 1, mens en sammenligning av konsentrasjonen av forbindelse A ved maksimum relaksasjonsgrad av CGP-12177A er vist i tabell 2. Forbindelse A viste en virkning som var 270 ganger sterkere enn med CGP-12177A (sammenligningsforbindelse). Likeledes er EC50og maksimum relaksasjonsgrad for det testede medikament i antagonismetesten ved kontraksjon med kaliumklorid vist i tabell 3, mens en sammenligning av konsentrasjonen av forbindelse A ved maksimum relaksasjonsgrad med CGP-12177A er vist i tabell 4. Forbindelse A viste en virkning som var 383 ganger sterkere enn med CGP-12177A (sammenligningsforbindelse). Relaxation rates depending on drug concentration of compound A, which is the active ingredient according to the present invention, and of the comparison compound are shown in figure 1 (antagonism test by contraction with carbachol) and figure 2 (antagonism test by contraction with potassium chloride). Furthermore, the EC50 and maximum degree of relaxation of the tested drug in the antagonism test by contraction with carbachol are shown in Table 1, while a comparison of the concentration of compound A at the maximum degree of relaxation of CGP-12177A is shown in Table 2. Compound A showed an effect that was 270 times stronger than with CGP-12177A (comparison compound). Likewise, the EC50 and maximum degree of relaxation of the tested drug in the antagonism test by contraction with potassium chloride are shown in Table 3, while a comparison of the concentration of compound A at the maximum degree of relaxation with CGP-12177A is shown in Table 4. Compound A showed an effect that was 383 times stronger than with CGP-12177A (comparison compound).
Eksempel 2 (Test for måling av rytmisk blærekontraksjon hos rotter) Example 2 (Test for measuring rhythmic bladder contraction in rats)
Testmetode Test method
Testen ble utført i henhold til European Journal of Pharmacology, 2000, vol. 407, side 175. The test was performed according to the European Journal of Pharmacology, 2000, vol. 407, page 175.
1. Målemetode 1. Measurement method
Hunnrotter (225 til 290 g) av Wistar-arten ble anvendt for testen. Under bedøvelse med uretan ble høyre og venstre urinleder snørt av og kuttet, og etter dette ble en poly-etylenkanyle ført inn fra ekstern urinmeatus og fiksert. Én ende av den fikserte kanyle ble forbundet med en trykkverdigiver via en tre-veis hane og trykket i blæren ble målt. Den andre ende ble forbundet med en sprøytepumpe og en fysiologisk saltvannsløsning ble kontinuerlig infusert med konstant hastighet i blæren, hvoretter det ble satt i gang rytmisk blærekontraksjon. Den kontinuerlige infusjon av fysiologisk saltvannsløsning ble stoppet etter at det var observert en rytmisk blærekontraksjon. Etter at den rytmiske blærekontraksjon hadde stabilisert seg, ble medikament eller vehikkel administrert fra et kateter for administrasjon av medikament, ført inn i femoralvenen. Female Wistar rats (225 to 290 g) were used for the test. Under anesthesia with urethane, the right and left ureters were ligated and cut, after which a polyethylene cannula was inserted from the external urinary meatus and fixed. One end of the fixed cannula was connected to a pressure transducer via a three-way stopcock and the pressure in the bladder was measured. The other end was connected to a syringe pump and a physiological saline solution was continuously infused at a constant rate into the bladder, after which rhythmic bladder contraction was initiated. The continuous infusion of physiological saline solution was stopped after a rhythmic bladder contraction was observed. After the rhythmic bladder contraction had stabilized, drug or vehicle was administered from a drug delivery catheter inserted into the femoral vein.
2. Medikament 2. Medication
Forbindelse A ble administrert intravenøst med økende doser i forholdet 3 (0,03, 0. 1, 0,3, 1 og 3 mg/kg). En gruppe som ble administrert vehikkel, ble anvendt som sammenligningsgruppe. Compound A was administered intravenously at increasing doses in the ratio of 3 (0.03, 0.1, 0.3, 1 and 3 mg/kg). A group that was administered vehicle was used as a comparison group.
3. Evaluerte parametre og statistisk analyse 3. Evaluated parameters and statistical analysis
Evaluerte parametre var antall ganger med kontraksjon og trykk ved blærekontraksjon i løpet av 10 minutter fra 5 til 15 minutter etter administrasjonen av medikamentet, og for hver gruppe ble evalueringene utført med n = 5. Resultatet er vist som middelverdi ± standardfeil og student-t-test ble utført for sammenligning av de to grupper. Evaluated parameters were the number of times of contraction and pressure during bladder contraction during 10 minutes from 5 to 15 minutes after the administration of the drug, and for each group the evaluations were carried out with n = 5. The result is shown as mean value ± standard error and student-t- test was performed for comparison of the two groups.
Resultater Results
Ved intravenøs administrasjon av forbindelse A avtok kontraksjonsfrekvensen med rytmisk blærekontraksjon på en doseavhengig måte (figur 3). Virkningen av minsket kontraksjonsfrekvens ved intravenøs injeksjon (i.v.) av 3 mg/kg av forbindelse A, var signifikant sammenlignet med sammenligningsgruppen. På den annen side påvirket forbindelse A ikke kontraksjonstrykket opp til en intravenøs administrasjon på 3 mg/kg (figur 4). Det faktum at det ikke var noen innvirkning på kontra ksjonstrykket, er en foretrukket egenskap ut fra det synspunkt at det ikke medfører tilbakeholdelse av urin eller at resultatet er tilbakeværende urin etter urinering. Upon intravenous administration of compound A, the contraction frequency with rhythmic bladder contraction decreased in a dose-dependent manner (Figure 3). The effect of decreased contraction frequency by intravenous injection (i.v.) of 3 mg/kg of compound A was significant compared to the comparison group. On the other hand, compound A did not affect the contraction pressure up to an intravenous administration of 3 mg/kg (Figure 4). The fact that there was no effect on the contraction pressure is a preferred feature from the point of view that it does not result in retention of urine or residual urine after urination.
At forbindelse A har en dempende virkning på kontraksjonsfrekvensen antas å skyldes en økning i blærevolumet ved at forbindelse A stimulerer en p3-reseptor som eksisterer i blæren. Det har vært antatt at en økning i funksjonelt blærevolum som viser urinvolumet som kan bli lagret i blæren, er klinisk nyttig for behandling av pasienter som lider av overaktiv blære, og derfor antas forbindelse A å være klinisk effektiv som en sammensetning for overaktiv blære. That compound A has a dampening effect on the contraction frequency is believed to be due to an increase in bladder volume by compound A stimulating a p3 receptor that exists in the bladder. It has been believed that an increase in functional bladder volume, which shows the volume of urine that can be stored in the bladder, is clinically useful for the treatment of patients suffering from overactive bladder, and therefore compound A is believed to be clinically effective as an overactive bladder composition.
Eksempel 3 (Test for måling av urineringsfunksjon hos modellrotte som lider av overaktiv blære forårsaket av syklofosfamid). Example 3 (Test for measurement of urinary function in model rat suffering from overactive bladder caused by cyclophosphamide).
Modell rotter med overaktiv blære forårsaket av syklofosfamid ble forberedt i henhold til British Journal of Pharmacology, 2000, vol. 130, side 331, og de følgende tester ble utført. Rat model of overactive bladder caused by cyclophosphamide was prepared according to British Journal of Pharmacology, 2000, vol. 130, page 331, and the following tests were performed.
Testmetode Test method
1. Målemetode 1. Measurement method
Hunnrotter (220 til 230 g) av Wistar-arten ble anvendt for testen. Under bedøvelse med natriumpentobarbital ble et kateter for infusjon av fysiologisk saltvannsløsning og for måling av trykk i blæren ført inn i blæren fra toppen av blæren og fiksert, mens et kateter for administrasjon av et medikament ble ført inn i karotidvenen og fiksert. Syklofosfamid Female Wistar rats (220 to 230 g) were used for the test. Under anesthesia with sodium pentobarbital, a catheter for infusion of physiological saline solution and for measurement of bladder pressure was inserted into the bladder from the top of the bladder and fixed, while a catheter for administration of a drug was inserted into the carotid vein and fixed. Cyclophosphamide
(CYP) ble administrert inn i abdominalkaviteten, og etter at rottene hadde kommet til seg selv, ble de returnert til et foringsbur. På den neste dag av operasjonen ble én ende av kateteret, som var ført inn i blæren hos rotten, forbundet med en sprøytepumpe via en tre-veis-hane og en fysiologisk saltvannsløsning ble kontinuerlig infusert, hvorved miksjonsrefleksen ble påvirket. Den andre ende var forbundet med en trykkverdigiver og trykket i blæren ble målt. Etter at miksjonsrefleksen var stabilisert, ble 1 mg/kg av forbindelse A administrert fra et kateter for administrasjon av medikament, som var ført inn i karotidvenen. (CYP) was administered into the abdominal cavity, and after the rats recovered, they were returned to a chow cage. On the next day of surgery, one end of the catheter, which had been inserted into the rat's bladder, was connected to a syringe pump via a three-way stopcock and a physiological saline solution was continuously infused, whereby the micturition reflex was affected. The other end was connected to a pressure transducer and the pressure in the bladder was measured. After the micturition reflex was stabilized, 1 mg/kg of compound A was administered from a drug delivery catheter inserted into the carotid vein.
2. Evaluerte parametre og statistisk analyse 2. Evaluated parameters and statistical analysis
Evaluert parameter var et midlere intervall for urinering fra administrasjon av medikamentet og inntil 30 minutter etter dette. Resultatet er vist som et midlere urineringsintervall etter administrasjon av medikamentet i forhold til det midlere urineringsintervall før administrasjon av medikamentet, hvor et midlere urineringsintervall i løpet av 30 minutter før administrasjon av medikamentet var definert som 100 %, og er vist som en middelverdi av n = 3. The evaluated parameter was an average interval for urination from the administration of the drug and up to 30 minutes after this. The result is shown as a mean urination interval after administration of the drug in relation to the mean urination interval before administration of the drug, where a mean urination interval during 30 minutes before administration of the drug was defined as 100%, and is shown as a mean value of n = 3.
Resultater Results
Som et resultat av intravenøs administrasjon av forbindelse A (1 mg/kg) ble miksjonsintervallet med overaktiv blære forårsaket av syklofosfamid, hvor rotter var modell, forlenget med 17,3% (figur 5). På grunnlag av dette faktum menes forbindelse A, som forlenget miksjonsintervallet hos de nevnte rotter som modell, å være klinisk effektiv som en sammensetning for overaktiv blære. As a result of intravenous administration of compound A (1 mg/kg), the micturition interval with overactive bladder caused by cyclophosphamide, in rats as a model, was prolonged by 17.3% (Figure 5). Based on this fact, compound A, which prolonged the micturition interval in the aforementioned model rats, is believed to be clinically effective as an overactive bladder composition.
Den aktive ingrediens ifølge den foreliggende oppfinnelse viser således en sterk blærerelakserende virkning i "test for relaksasjon av glatte muskler i isolert rotteblære", reduksjon i kontraksjonsfrekvensen ved rytmisk blærekontraksjon på en doseavhengig måte i "test for måling av rytmisk blærekontraksjon hos rotte", og den forlenger miksjonsintervallet i "test for måling av miksjonsfunksjon ved syklofosfamid-bevirket overaktiv blære i rotte som modell", hvorved den er klinisk anvendelig som en sammensetning for overaktiv blære. I tillegg til overaktiv blære som et resultat av godartet prostatahyperplasi, kan den også bli anvendt som en sammensetning for overaktiv blære i sammenheng med urineringstrang, urininkontinens og pollakiuri. The active ingredient according to the present invention thus shows a strong bladder relaxant effect in "test for relaxation of smooth muscles in isolated rat bladder", reduction in the contraction frequency in rhythmic bladder contraction in a dose-dependent manner in "test for measurement of rhythmic bladder contraction in rats", and the prolongs the micturition interval in the "test for measurement of micturition function in cyclophosphamide-induced overactive bladder in the rat as a model", whereby it is clinically applicable as a composition for overactive bladder. In addition to overactive bladder as a result of benign prostatic hyperplasia, it can also be used as a composition for overactive bladder in connection with urge to urinate, urinary incontinence and pollakiuria.
Eksempel 4 (Formuleringseksempel) Example 4 (Formulation example)
Formuleringseksempel for oralt middel Formulation example for oral agent
Tablett 100 mg Tablet 100 mg
Den aktive ingrediens ifølge den foreliggende oppfinnelse (200,0 g) og 399,0 g laktose ble blandet i en polyetylenpose. Blandingen ble mikset og desintegrert i en laboratoriemølle (produsert av Hosokawa Micron). Den desintegrerte blanding (450,0 g) og 60,1 g maisstivelse ble blandet homogent i en beleggingsapparatur med fluidisert granulering (produsert av Ogawara Seisakusho). For å oppnå granulering ble det dusjet på 192 g av en 10 % oppløsning av hydroksypropylcellulose. Etter å ha fått tørke, ble dette passert gjennom en sikt med 0,850 mm åpninger, det ble tilsatt magnesiumstearat og av blandingen ble det fremstilt tabletter, hver på 350 mg, i en roterende tabletteringsmaskin (produsert av Hata Tekkosho) ved å anvende et stempel på 9,0 mm x 10,8 R. Tablettene ble dusjet med 150 g av beleggingsløsning som inneholdt 8,7 g hydroksypropylmetylcellulose, 1,2 g polyetylenglykol 6000, 4,8 g titanoksid og 0,3 g talkum i en beleggingsapparatur (produsert av Freund Sangyo), for å oppnå filmovertrukne tabletter hvor hver tablett var overtrukket med 15 mg. The active ingredient according to the present invention (200.0 g) and 399.0 g of lactose were mixed in a polyethylene bag. The mixture was mixed and disintegrated in a laboratory mill (manufactured by Hosokawa Micron). The disintegrated mixture (450.0 g) and 60.1 g of corn starch were mixed homogeneously in a fluidized granulation coating apparatus (manufactured by Ogawara Seisakusho). To achieve granulation, 192 g of a 10% solution of hydroxypropyl cellulose was showered. After being allowed to dry, this was passed through a sieve with 0.850 mm apertures, magnesium stearate was added and the mixture was made into tablets, each of 350 mg, in a rotary tableting machine (manufactured by Hata Tekkosho) using a stamp on 9.0 mm x 10.8 R. The tablets were showered with 150 g of coating solution containing 8.7 g of hydroxypropylmethyl cellulose, 1.2 g of polyethylene glycol 6000, 4.8 g of titanium oxide and 0.3 g of talc in a coating apparatus (manufactured by Freund Sangyo), to obtain film-coated tablets where each tablet was coated with 15 mg.
Industriell anvendelighet Industrial applicability
Som nevnt over viste (R)-2-(2-aminotiazol-4-yl)-4'-[2-[(2-hydroksy-2-fenyl-etyl)amino]etyl]eddiksyreanilid, eller et salt av dette, som en aktiv ingrediens ifølge den foreliggende oppfinnelse, en signifikant sterk relaksasjonsvirkning sammenlignet med sammenligningsforbindelsen i "relaksasjonstest for glatte muskler i isolert rotteblære". Videre minsket den kontraksjonsfrekvensen ved rytmisk blærekontraksjon på en doseavhengig måte i "test for måling av rytmisk blærekontraksjon hos rotte". I tillegg så forlenget den miksjonsintervallet med overaktiv blære forårsaket av syklofosfamid i rotte som modell i "test for måling av miksjonsfunksjon for syklofosfamid-frembragt overaktiv blære i rotte som modell". As mentioned above, (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenyl-ethyl)amino]ethyl]acetic anilide, or a salt thereof, as an active ingredient according to the present invention, a significantly strong relaxation effect compared to the comparison compound in the "smooth muscle relaxation test in isolated rat bladder". Furthermore, it decreased the contraction frequency of rhythmic bladder contraction in a dose-dependent manner in the "rat rhythmic bladder contraction test". In addition, it prolonged the micturition interval with cyclophosphamide-induced overactive bladder in the rat model in the "test for measurement of micturition function for cyclophosphamide-induced overactive bladder in the rat model".
Følgelig kan (R)-2-(2-aminotiazol-4-yl)-4'-[2-[(2-hydroksy-2-fenyletyl)amino]-etyl]eddiksyreanilid eller et salt av dette, som er en aktiv ingrediens ifølge den foreliggende oppfinnelse, anvendes som en sammensetning for anvendelse ved behandling av overaktiv blære. I tillegg til overaktiv blære som et resultat av godartet prostatisk hyperplasi, så kan det også bli anvendt som en sammensetning for anvendelse ved behandling av overaktiv blære i sammen-heng med urineringstrang, urininkontinens og pollakiuri. Accordingly, (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]-ethyl]acetic anilide or a salt thereof, which is an active ingredient according to the present invention, is used as a composition for use in the treatment of overactive bladder. In addition to overactive bladder as a result of benign prostatic hyperplasia, it can also be used as a composition for use in the treatment of overactive bladder in connection with urge to urinate, urinary incontinence and pollakiuria.
Kort beskrivelse av tegningene Brief description of the drawings
Figur 1: Virkning av forbindelse A og av kontrollforbindelse ved test for relaksasjon av glatte muskler i rotteblære (antagonismetest for kontraksjon med karbachol). Figur 2: Virkning av forbindelse A og av kontrollforbindelse ved test for relaksasjon av glatte muskler i rotteblære (antagonismetest for kontraksjon med kaliumklorid). Figur 3: Virkning av forbindelse A på rytmisk blærekontraksjon (virkning på kontraksjonsfrekvens (<*>: p < 0,05)). Figur 4: Virkning av forbindelse A på rytmisk blærekontraksjon hos rotte (virkning på kontraksjonstrykk). Figur 5: Virkning av forbindelse A på miksjonsfunksjon med overaktiv blære forårsaket av syklofosfamid med rotte som modell (viser urineringsintervallet etter administrasjon av et medikament hvor urineringsintervallet før administrasjonen av medikamentet var satt til 100 %). Figure 1: Effect of compound A and of control compound in test for relaxation of smooth muscles in rat bladder (antagonism test for contraction with carbachol). Figure 2: Effect of compound A and of control compound in test for relaxation of smooth muscles in rat bladder (antagonism test for contraction with potassium chloride). Figure 3: Effect of compound A on rhythmic bladder contraction (effect on contraction frequency (<*>: p < 0.05)). Figure 4: Effect of compound A on rhythmic bladder contraction in the rat (effect on contraction pressure). Figure 5: Effect of compound A on micturition function with overactive bladder caused by cyclophosphamide with a rat as a model (shows the micturition interval after administration of a drug where the micturition interval before the administration of the drug was set to 100%).
Claims (6)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002323792 | 2002-11-07 | ||
PCT/JP2003/014065 WO2004041276A1 (en) | 2002-11-07 | 2003-11-04 | Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient |
Publications (3)
Publication Number | Publication Date |
---|---|
NO20052691D0 NO20052691D0 (en) | 2005-06-06 |
NO20052691L NO20052691L (en) | 2005-07-15 |
NO334948B1 true NO334948B1 (en) | 2014-08-04 |
Family
ID=32310425
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO20052691A NO334948B1 (en) | 2002-11-07 | 2005-06-06 | Composition for use in the therapeutic treatment of overactive bladder, comprising acetic acid aniline derivative as active ingredient |
NO2015001C NO2015001I2 (en) | 2002-11-07 | 2015-01-19 | Mirabegron or a salt thereof |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO2015001C NO2015001I2 (en) | 2002-11-07 | 2015-01-19 | Mirabegron or a salt thereof |
Country Status (28)
Country | Link |
---|---|
US (5) | US7750029B2 (en) |
EP (1) | EP1559427B1 (en) |
JP (1) | JP3815496B2 (en) |
KR (1) | KR100967070B1 (en) |
CN (1) | CN100406011C (en) |
AT (1) | ATE500827T1 (en) |
AU (1) | AU2003284700B2 (en) |
BE (1) | BE2013C040I2 (en) |
BR (1) | BR0316080A (en) |
CA (1) | CA2503570C (en) |
CY (2) | CY1111399T1 (en) |
DE (1) | DE60336334D1 (en) |
DK (1) | DK1559427T3 (en) |
ES (1) | ES2360353T3 (en) |
FR (1) | FR13C0032I2 (en) |
HU (1) | HUS1300027I1 (en) |
IL (1) | IL168121A (en) |
LU (1) | LU92218I2 (en) |
MX (1) | MXPA05004925A (en) |
NL (1) | NL300599I2 (en) |
NO (2) | NO334948B1 (en) |
NZ (1) | NZ539577A (en) |
PL (1) | PL211687B1 (en) |
PT (1) | PT1559427E (en) |
RU (1) | RU2321401C2 (en) |
SI (1) | SI1559427T1 (en) |
WO (1) | WO2004041276A1 (en) |
ZA (1) | ZA200503510B (en) |
Families Citing this family (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10351271A1 (en) * | 2003-10-31 | 2005-06-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical composition for the treatment of stress incontinence and / or mixed incontinence |
SI2216021T1 (en) * | 2007-11-02 | 2013-01-31 | Astellas Pharma Inc. | Pharmaceutical composition for treating overactive bladder |
CA2709727A1 (en) * | 2007-12-21 | 2009-07-02 | Astellas Pharma Inc. | Pharmaceutical composition for improving lower urinary tract symptoms |
PE20091825A1 (en) * | 2008-04-04 | 2009-12-04 | Merck & Co Inc | HYDROXIMETHYL PYRROLIDINES AS AGONISTS OF THE BETA 3 ADRENERGIC RECEPTOR |
TWI478712B (en) * | 2008-09-30 | 2015-04-01 | Astellas Pharma Inc | Pharmaceutical composition for modified release |
EP2363397A4 (en) * | 2008-11-07 | 2012-07-11 | Dainippon Sumitomo Pharma Co | Novel useful therapeutic agent for lower urinary tract symptom |
US8586760B2 (en) * | 2009-06-15 | 2013-11-19 | Auspex Pharmaceuticals, Inc. | Aminothiazole modulators of beta-3-adrenoreceptor |
WO2011122523A1 (en) * | 2010-03-29 | 2011-10-06 | アステラス製薬株式会社 | Controlled release pharmaceutical composition |
PL2554168T3 (en) | 2010-03-29 | 2018-05-30 | Astellas Pharma Inc. | Controlled release pharmaceutical composition |
US9655885B2 (en) | 2011-05-18 | 2017-05-23 | Dr. Reddy's Laboratories Ltd. | Amorphous mirabegron and processes for crystal forms of mirabegron |
WO2012156998A2 (en) * | 2011-05-18 | 2012-11-22 | Dr. Reddy's Laboratories Limited | Amorphous mirabegron and processes for crystal forms of mirabegron |
US20150031734A1 (en) | 2012-03-30 | 2015-01-29 | Astellas Pharma Inc. | Pharmaceutical composition containing mirabegron |
BR112015004244A2 (en) | 2012-08-31 | 2017-07-04 | Astellas Pharma Inc | orally administered medical composition |
WO2014132270A2 (en) * | 2013-02-27 | 2014-09-04 | Msn Laboratories Limited | Process for the preparation of 2-(2-aminothiazol-4-yl)-n-[4-(2-{[(2r)-2-hydroxy-2-phenyl ethyl]amino}ethyl)phenyl]acetamide monohydrochloride, its intermediates and polymorph thereof |
CN103193730A (en) * | 2013-04-17 | 2013-07-10 | 苏州永健生物医药有限公司 | Synthesis method of mirabegron |
CN103193658A (en) * | 2013-04-18 | 2013-07-10 | 苏州永健生物医药有限公司 | Synthesis method of (R)-2-p-nitrobenzene ethylamine-1-phenethyl alcohol and salt thereof |
CN103232368B (en) * | 2013-04-18 | 2015-08-12 | 苏州永健生物医药有限公司 | A kind of synthetic method of (R)-4-nitrophenethyl-(2-hydroxyl-2-styroyl)-t-butyl carbamate |
CN103232352B (en) * | 2013-05-11 | 2015-12-23 | 苏州永健生物医药有限公司 | (R)-4-(2-(2-hydroxyl-2-phenylethylamine base) ethyl) anilino carboxylate |
AU2014293141A1 (en) * | 2013-07-23 | 2016-02-18 | Serenity Pharmaceuticals Llc | Methods and compositions comprising desmopressin in combination with a beta-3 adrenergic receptor agonist |
ITMI20131653A1 (en) * | 2013-10-07 | 2015-04-08 | Dipharma Francis Srl | CRYSTALLINE FORMS OF AN ADRENERGIC AGONIST |
RU2550968C1 (en) * | 2013-11-29 | 2015-05-20 | Федеральное государственное бюджетное учреждение "Научный центр акушерства, гинекологии и перинатологии имени академика В.И. Кулакова" Министерства здравоохранения Российской Федерации | Integrated method of treating female patients suffering from chronic recurrent cystitis and refractory overactive bladder |
WO2015155664A1 (en) * | 2014-04-08 | 2015-10-15 | Suven Life Sciences Limited | An improved process for the preparation of 2-(2-aminothiazol-4-yl)-n-[4-(2-[[(2r)-2-hydroxy-2- phenylethyl]amino]-ethyl)phenyl]acetamide |
WO2015162536A1 (en) * | 2014-04-22 | 2015-10-29 | Calyx Chemicals And Pharmaceuticals Ltd. | Novel process for preparation of mirabegron and it's intermediate |
CN104016943A (en) * | 2014-05-23 | 2014-09-03 | 苏州凯瑞医药科技有限公司 | Synthetic method of mirabegron |
CN104016877B (en) * | 2014-06-13 | 2017-02-15 | 南京海融制药有限公司 | Acetylaniline compounds and application thereof in preparation of mirabegron |
CN104230840A (en) * | 2014-09-05 | 2014-12-24 | 安徽联创药物化学有限公司 | Synthesis method of mirabegron |
EP3220942B1 (en) | 2014-11-20 | 2022-04-27 | Serenity Pharmaceuticals LLC | Compositions comprising low dose desmopressin in combination with an alpha-adrenergic receptor antagonist |
CN104496841B (en) * | 2014-11-26 | 2017-01-25 | 南京工业大学 | Method for synthesizing mirabegron intermediate |
CN104744292A (en) * | 2015-03-11 | 2015-07-01 | 南京工业大学 | Preparation method of (R)-2-((4=ethylnitrobenzene) amino)-2-oxo-1-phenethyl acetate or derivate thereof |
JP2018090490A (en) | 2015-03-31 | 2018-06-14 | アステラス製薬株式会社 | Mirabegron-containing pharmaceutical composition |
JP6618736B2 (en) | 2015-09-01 | 2019-12-11 | 沢井製薬株式会社 | Mirabegron-containing tablet, method for producing mirabegron-containing preparation, and method for producing mirabegron-containing granulated product |
CN106278909B (en) * | 2016-08-12 | 2022-07-15 | 浙江华海药业股份有限公司 | Post-treatment method of mirabegron intermediate |
EP3489224A1 (en) | 2017-02-14 | 2019-05-29 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Mirabegron prodrugs |
KR102051132B1 (en) * | 2017-03-17 | 2019-12-02 | 주식회사 종근당 | Pharmaceutical composition for controlled release comprising Mirabegron or its salts |
KR101868438B1 (en) | 2017-04-13 | 2018-06-20 | (주) 성운파마코피아 | Method for preparing amide derivatives |
US11123320B2 (en) | 2017-05-31 | 2021-09-21 | Sbi Pharmaceuticals, Co., Ltd. | Prophylactic or therapeutic agent for hyperaciive bladder |
KR102398639B1 (en) | 2017-06-20 | 2022-05-17 | (주) 성운파마코피아 | Salts of amide derivatives and method for preparing the same |
WO2019013583A2 (en) | 2017-07-14 | 2019-01-17 | 주식회사 대웅제약 | Pharmaceutical preparation and preparation method therefor |
KR101937713B1 (en) | 2017-07-14 | 2019-01-14 | 주식회사 대웅제약 | Pharmaceutical formulation and preparation method for the same |
KR20200117091A (en) | 2019-04-02 | 2020-10-14 | 제이투에이치바이오텍 (주) | Prodrug compound of mirabegron and its medical use for treating or alleviating overactive bladder diseases |
EP3722285B1 (en) | 2020-04-08 | 2022-03-30 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Process for preparing mirabegron enacarbil |
CN113816864B (en) * | 2020-06-18 | 2024-03-29 | 南京正大天晴制药有限公司 | Preparation method of (R) -2-hydroxy-N- [2- (4-aminophenyl) ethyl ] -2-phenethylamine |
KR20220081033A (en) | 2020-12-08 | 2022-06-15 | 주식회사 한서켐 | Manufacturing method of α-type crystalline Mirabegron |
EP4338729A1 (en) | 2022-09-19 | 2024-03-20 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A tablet comprising mirabegron |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH07119189B2 (en) | 1989-09-28 | 1995-12-20 | 北陸製薬株式会社 | Optically active benzyl alcohol derivative and its use |
GB9107827D0 (en) | 1991-04-12 | 1991-05-29 | Fujisawa Pharmaceutical Co | New ethanolamine derivatives,processes for the preparation thereof and pharmaceutical composition comprising the same |
IL104567A (en) | 1992-02-03 | 1997-03-18 | Fujisawa Pharmaceutical Co | Ethanolamine derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same |
JPH06293664A (en) | 1993-04-05 | 1994-10-21 | Fujisawa Pharmaceut Co Ltd | New pharmaceutical use of beta3-adrenergic agent |
AU6581294A (en) | 1993-04-26 | 1994-11-21 | Fujisawa Pharmaceutical Co., Ltd. | Ethanolamine derivatives useful for the treatment of gastrointestinal disorders |
JPH07228543A (en) | 1994-02-16 | 1995-08-29 | Fujisawa Pharmaceut Co Ltd | New pharmaceutical use of beta3-adrenalin agonist |
WO1997015549A1 (en) | 1995-10-26 | 1997-05-01 | Tokyo Tanabe Company Limited | PHENYLETHANOLAMINE COMPOUNDS USEFUL AS β3 AGONIST, PROCESS FOR PRODUCING THE SAME, AND INTERMEDIATES IN THE PRODUCTION OF THE SAME |
US6204285B1 (en) | 1996-07-01 | 2001-03-20 | Sepracor Inc. | Methods and compositions for treating urinary incontinence using enantiomerically enriched (R,R)-glycopyrrolate |
JP4685201B2 (en) | 1996-08-19 | 2011-05-18 | キッセイ薬品工業株式会社 | Preventive and therapeutic agent for frequent urination and incontinence |
EP1014957A4 (en) | 1997-08-28 | 2004-01-28 | Afferon Corp | Urinary incontinence therapy |
ID23989A (en) * | 1997-10-17 | 2000-06-14 | Yamanouchi Pharma Co Ltd | THE AMIDA DOWNS OR THE SALT |
CA2315235C (en) | 1997-12-18 | 2009-07-28 | Kissei Pharmaceutical Co., Ltd. | Phenylaminoalkylcarboxylic acid derivatives and medicinal compositions containing the same |
US6696489B1 (en) | 1998-04-14 | 2004-02-24 | Kissei Pharmaceutical Co., Ltd. | 2-Methylpropionic acid derivatives and medicinal compositions containing the same |
MY126489A (en) | 1998-07-08 | 2006-10-31 | Kissei Pharmaceutical | Phenoxyacetic acid derivatives and medicinal compositions containing the same |
WO2000047771A2 (en) | 1999-02-12 | 2000-08-17 | Genset | Biallelic markers derived from genomic regions carrying genes involved in arachidonic acid metabolism |
GB2356197A (en) | 1999-10-12 | 2001-05-16 | Merck & Co Inc | Amide derivatives as beta 3 agonists |
JP2001114736A (en) * | 1999-10-19 | 2001-04-24 | Kissei Pharmaceut Co Ltd | 2-aminopropanol derivative |
AU2710301A (en) | 2000-01-28 | 2001-08-07 | Asahi Kasei Kabushiki Kaisha | Novel remedies with the use of beta3 agonist |
AUPQ585000A0 (en) * | 2000-02-28 | 2000-03-16 | Fujisawa Pharmaceutical Co., Ltd. | Aminoalcohol derivatives |
AUPQ841300A0 (en) | 2000-06-27 | 2000-07-20 | Fujisawa Pharmaceutical Co., Ltd. | New aminoalcohol derivatives |
AR035605A1 (en) | 2000-12-11 | 2004-06-16 | Bayer Corp | DERIVATIVES OF AMINOMETIL CHROMANO DI-SUBSTITUTES, A METHOD FOR THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS AND THE USE OF SUCH DERIVATIVES FOR THE MANUFACTURE OF USEFUL MEDICINES AS BETA-3-ADRENE-RECEPTORS AGONISTS |
US7342117B2 (en) | 2001-10-30 | 2008-03-11 | Astellas Pharma Inc. | α-form or β-form crystal of acetanilide derivative |
WO2006102029A2 (en) * | 2005-03-21 | 2006-09-28 | Dov Pharmaceutical, Inc. | Methods and compositions for the treatment of urinary incontinence |
-
2003
- 2003-11-04 CA CA2503570A patent/CA2503570C/en not_active Expired - Lifetime
- 2003-11-04 WO PCT/JP2003/014065 patent/WO2004041276A1/en active Application Filing
- 2003-11-04 AU AU2003284700A patent/AU2003284700B2/en not_active Expired
- 2003-11-04 CN CNB2003801028894A patent/CN100406011C/en not_active Expired - Lifetime
- 2003-11-04 DK DK03770134.9T patent/DK1559427T3/en active
- 2003-11-04 ZA ZA200503510A patent/ZA200503510B/en unknown
- 2003-11-04 RU RU2005117367/15A patent/RU2321401C2/en active
- 2003-11-04 US US10/534,290 patent/US7750029B2/en not_active Ceased
- 2003-11-04 PL PL376771A patent/PL211687B1/en unknown
- 2003-11-04 SI SI200331996T patent/SI1559427T1/en unknown
- 2003-11-04 AT AT03770134T patent/ATE500827T1/en active
- 2003-11-04 JP JP2004549600A patent/JP3815496B2/en not_active Expired - Lifetime
- 2003-11-04 ES ES03770134T patent/ES2360353T3/en not_active Expired - Lifetime
- 2003-11-04 PT PT03770134T patent/PT1559427E/en unknown
- 2003-11-04 EP EP03770134A patent/EP1559427B1/en not_active Expired - Lifetime
- 2003-11-04 KR KR1020057008158A patent/KR100967070B1/en active IP Right Review Request
- 2003-11-04 US US13/542,308 patent/USRE44872E1/en not_active Expired - Lifetime
- 2003-11-04 BR BR0316080-7A patent/BR0316080A/en not_active Application Discontinuation
- 2003-11-04 NZ NZ539577A patent/NZ539577A/en not_active IP Right Cessation
- 2003-11-04 MX MXPA05004925A patent/MXPA05004925A/en active IP Right Grant
- 2003-11-04 DE DE60336334T patent/DE60336334D1/en not_active Expired - Lifetime
- 2003-11-04 US US10/534,290 patent/US20060115540A1/en active Granted
-
2005
- 2005-04-19 IL IL168121A patent/IL168121A/en active IP Right Grant
- 2005-06-06 NO NO20052691A patent/NO334948B1/en not_active IP Right Cessation
-
2008
- 2008-12-12 US US12/333,357 patent/US20090093529A1/en not_active Abandoned
-
2011
- 2011-04-18 CY CY20111100395T patent/CY1111399T1/en unknown
- 2011-05-27 US US13/117,638 patent/US8835474B2/en not_active Expired - Lifetime
-
2013
- 2013-06-17 LU LU92218C patent/LU92218I2/en unknown
- 2013-06-19 HU HUS1300027C patent/HUS1300027I1/en unknown
- 2013-06-19 FR FR13C0032C patent/FR13C0032I2/en active Active
- 2013-06-19 CY CY2013023C patent/CY2013023I2/en unknown
- 2013-06-20 NL NL300599C patent/NL300599I2/nl unknown
- 2013-06-20 BE BE2013C040C patent/BE2013C040I2/fr unknown
-
2015
- 2015-01-19 NO NO2015001C patent/NO2015001I2/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
NO334948B1 (en) | Composition for use in the therapeutic treatment of overactive bladder, comprising acetic acid aniline derivative as active ingredient | |
US20090105298A1 (en) | Pharmaceutical composition for therapy of interstitial cystitis | |
US8101580B2 (en) | Therapeutic agent for irritable bowel syndrome | |
JPWO2006011397A1 (en) | Drugs for the prevention or treatment of diabetes | |
US20050267195A1 (en) | Drug composition for blood sugar control | |
US20090018181A1 (en) | Drug composition for prevention or inhibition of advance of diabetic complication | |
JP2000239163A (en) | Intestinal disease therapeutic agent | |
JPWO2005117855A1 (en) | Drugs for the prevention or treatment of diabetes | |
US20060025478A1 (en) | Medicine for prevention or treatment of diabetes |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
SPCF | Filing of supplementary protection certificate |
Free format text: PRODUCT NAME: BETMIGA - MIRABEGRON; REG. NO/DATE: EU/1/12/809/001-014 20130117 Spc suppl protection certif: 2015001 Filing date: 20150119 |
|
SPCG | Granted supplementary protection certificate |
Free format text: PRODUCT NAME: MIRABEGRON ELLER SALTER DERAV; REG. NO/DATE: EU/1/12/809/001-014 20130117 Spc suppl protection certif: 2015001 Filing date: 20150119 |
|
SPCS | Change of name or address of the owner of a supplementary protection certificate |
Owner name: ASTELLAS PHARMA INC, JP Spc suppl protection certif: 2015001 |
|
MK1K | Patent expired |